Hormone preparation and method

ABSTRACT

This invention is concerned with a contraceptive formulation and a method of contraception which employs a combination of estrogen and progestin and wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity. The invention also concerns a hormonal replacement formulation and method for use in menopausal or castrate women which employs a similar combination of estrogen and progestin.

This application is a division of my co-pending application Ser. No.07/788,259, filed Nov. 5, 1991, now U.S. Pat. No. 5,276,022, which is adivision of Ser. No. 07/515,691, filed Apr. 26, 1990, now U.S. Pat. No.5,108,995, which is a continuation of Ser. No. 07/247,861, filed Sep.22, 1988, now abandoned.

This invention is concerned with a contraceptive formulation and amethod of contraception which employs a combination of estrogen andprogestin and wherein a short period of relatively dominant estrogenicactivity alternates with a short period of relatively dominantprogestagenic activity. Also described are formulations which employsimilar hormone combinations for hormonal replacement therapy formenopausal or castrate women.

Currently on the market there are a number of contraceptive formulationswhich can be classified readily into several general types. The first ofthese are known as monophasic formulations. These contain a constantamount of estrogen and progestin. Nuisance side effects with these pillsdepend on the balance between the estrogen and progestin component ofthe pill. For example, with a relatively dominant progestin pill, theformulation will, over time, result in a depletion of both estrogen andprogestin receptors. The result which might be expected is anunderstimulated or atrophic endometrium which may eventually causeeither on-pill amenorrhea or breakthrough bleeding or spotting due topoor epithelialization. On the other hand, with a relatively dominantestrogenic preparation, it is possible that prolonged use could resultin endometrial growth with the development of unsupported fragile stromaand subsequent spotting or breakthrough bleeding.

Newer formulations known as triphasics have varying levels of estrogenand progestin; in most cases consisting of relatively constant levels ofestrogen with a step-wise increase in progestin throughout the cycle.This pattern of estrogen and progestin administration results in arelatively dominant estrogenic formulation at the beginning of thepackage with increasing progestagenic activity toward the end of thepackage. Endometrial stability may be better with these pills since theestrogenic activity at the beginning of the package induces bothestrogen and progestin receptors making the endometrium sensitive to theincreased levels of progestin towards the end of the package. Theprogestin activity produces denser, more stable endometrial stromaalthough the relatively long duration of progestin exposure, toward theend of the package, may still lead to decreased estrogen and progestinreceptors and activity. A significant problem with this type offormulation is the low dose of steroids at the beginning of the packagewhich makes these pills vulnerable to drug interactions or missed pillswhich may lead to breakthrough ovulation. The beginning of the packageis the critical time in terms of breakthrough ovulation since the userhas just completed a 7 day drug-free interval during which folliculardevelopment may begin. Even if pregnancy does not occur, breakthroughovulation can lead to poor cycle control.

Estrogen replacement therapy is warranted in menopausal women forseveral reasons. Estrogen replacement will relieve hot flushes and thisrelief of flushes and night sweats improves sleep patterns andcontributes to the patient's general feeling of well-being (see CampbellS., Whitehead M. I. Estrogen therapy and the menopausal syndrome. InClinics in Obstetrics and Gynecology: Volume 4. The Menopause. Edited byR. B. Greenblatt, J. W. W. Studd, London, W. B. Saunders, 1977, pages31-47; Erlik Y., Tataryn I. V., Meldrum D. R. et al. Association ofwaking episodes with menopausal hot flushes. JAMA 24:1741, 1981).Estrogen replacement protects against postmenopausal loss of calciumfrom the skeleton, especially from vertebral bodies, preventing crushfractures and loss of body height (see Lindsay R., Hart D. M., Forrest,C. et al. Prevention of spinal osteoporosis in oophorectomized women.Lancet 2:1151, 1980). Several studies have now reported that long-termestrogen therapy is also associated with a reduction in the incidence ofclassical osteoporotic fractures of the forearm and hip (see Hutchinson,T. A., Polansky, S. M., Finestein, A. Postmenopausal estrogens protectagainst fractures of hip and distal radius. Lancet 2:706, 1979;Paganini-Hill, A., Ross, R. K., Gerkins, V. R., et al. A case controlstudy of menopausal estrogen therapy in hip fractures. Annals ofInternal Medicine 95:28, 1981; Weiss N. S., Ure C. L., Ballard J. H. etal. Decreased risk of fractures of the hip and lower forearm withpostmenopausal use of estrogen. New England Journal of Medicine303:1195, 1980). Another beneficial effect of long-term estrogen use isthe reduction of the risk of death from ischemic heart disease probablymediated by changes in blood lipoprotein concentrations (see Ross R. K.,Paganini-Hill A., Mack T. M. et al. Menopausal estrogen therapy andprotection from ischemic heart disease. Lancet 1:858, 1981). Estrogenreplacement has also been shown to improve the vascularity and health ofthe vaginal mucosa and urinary tract. The only major risk factorassociated with estrogen administration in the doses required to relievemenopausal symptoms, is hyperstimulation of the endometrium and anincreased risk of endometrial cancer (see Cramer D. W., Knapp R. C.Review of epidemiologic studies of endometrial cancer and exogenousestrogen. Obstetrics and Gynecology 54:521, 1979; Shapiro S., CoughmanD. W., Sloan D., et al. Recent and past use of conjugated estrogens inrelation to adenocarcinoma of the endometrium. New England Journal ofMedicine 303:485, 1980).

Estrogens predispose to cancer of the endometrium by stimulating cellmitosis and proliferation and increasing the levels of DNA synthesis andnuclear estradiol receptors in the endometrium (see Whitehead M. I.,Townsen P. T., Pryce-Davies J., et al. Effects estrogens and progestinson the biochemistry and morphology of the postmenopausal endometrium.New England Journal of Medicine 305:1599, 1981; Whitehead M. I., TownsenP. T., Pryce-Davies J., et al. Actions of progestins on the morphologyand biochemistry of the endometrium of postmenopausal women receivinglow dose estrogen therapy. American Journal of Obstetrics andGynecology, 142:791, 1982).

The addition of a progestin for 13 days each month has been demonstratedto protect the endometrium from these stimulatory effects of estrogen(see Gambrill R. D., Jr., Massey F. M., Castaneda et al. Use of theprogestogen challenge test to reduce the risk of endometrial cancer.Obstetrics and Gynecology 55:732, 1980; Studd J. W. W., Thom M. H.,Patterson M. E. L., Wade-Evans T. The prevention and treatment ofendometrial pathology in postmenopausal women receiving exogenousestrogens. In: Pasetto N., Paoletti R., Armbus J. L., Editors. Themenopause and postmenopause. Lancester MPT Press. 127,1980).

The addition of a progestin protects the endometrium by reducing nuclearestradiol receptor concentration and thereby decreases nuclear estrogenbioavailability resulting in an antimitotic effect and lowering DNAsynthesis. Progestins also increase the activity of endometrialestradiol-17beta-dehydrogenase, an enzyme which metabolizes estradiol toestrone, a less potent estrogen (see Whitehead M. I., Townsen P. T.,Pryce-Davies J. Effects of estrogens and progestins on the biochemistryand morphology of the postmenopausal endometrium. New England Journal ofMedicine. 305:1599, 1981; King R. J. B., Townsen P. T., Sittle N. C., etal. Regulation of estrogen and progesterone receptor levels inepithelium and stroma from pre and postmenopausal endometria. Journal ofSteroids and Biochemistry, 16:21, 1982; Gurpide E. Enzymatic modulationof hormonal action at the target tissue. Journal of Toxicology andEnvironmental Health, 4:249, 1978). The addition of progestin toestrogen replacement therapy may also result in an increase in bone masswhen started within 3 years of the menopause (see Nachtigall L. E.,Nachtigall R. H., Nachtigall R. D., et al. Estrogen replacement therapy:A 10 year prospective study in relationship to osteoporosis. Obstetricsand Gynecology 53:277, 1979; Lindsay R., Hart D. M., Forrest C., et al.Prevention of spinal osteoporosis in oophorectomized women. Lancet2:1151, 1980). However, concerns have been expressed about the potentialadverse effects of progestin in suppressing high density lipoproteincholesterol concentrations (see Hirvonen E., Malkonen M., Manninen V.Effects of different progestogens on lipoproteins during postmenopausalreplacement therapy. New England Journal of Medicine 304:560, 1981).This cholesterol fraction appears to have a protective effect againstischemic heart disease and atherosclerosis. The lowering of HDLcholesterol by progestin could negate the long-term beneficial effectsof estrogen in reducing the incidence of myocardial infraction. Otherside effects of progestins include acne, breast tenderness, depressionand irritability (see Barranco V. P. Effect of androgen dominant andestrogen dominant oral contraceptives on acne. Cutis 14:384, 1974; RoyalCollege of General Practioners. Oral Contraceptives and Health: AnInterim Report. New York: Pitman, 1974). Since the side effects ofprogestins appear to be dose dependent, the dose of progestin used withpostmenopausal estrogen replacement should be the minimum necessary toachieve endometrial protection. (see Padwick M. L., Pryce-Davies J.,Whitehead M. I. A simple method for determining the optimal dosage ofprogestin in postmenopausal women receiving estrogens. New EnglandJournal of Medicine 315:930, 1986).

The biological effects of both estrogen and progestin in target tissuessuch as the endometrium are dependent on the levels of estrogen andprogestin receptors. Both estrogen and progestins exert a modulatinginfluence on the levels of their own receptors. For example, in theluteal phase of the menstrual cycle, serum progesterone levels increaseand progesterone mediated secretory changes occur in the uterineendometrium. The presence of progesterone receptors has been shown to bea necessary prerequisite for progesterone action in the endometrium (seeWalters M. R. and Clark J. H. Relationship between the quantity ofprogesterone receptors and the antagonism of estrogen-induceduterotropic response. Endocrinology 105:382, 1979) and it is welldocumented that estrogen priming in the follicular phase of the cycle isresponsible for the development of both estrogen and progesteronereceptors (see Bayard F., Damilano S., Robel P. and Baulieu E. E.Cytoplasmic and nuclear estradiol and progesterone receptors in humanendometrium. Journal Clinical Endocrinology and Metabolism 46:635,1978). On the other hand, progesterone exerts a negative feedback effecton its own receptor (see Tseng L. and Gurpide E. Effects of progestinson estradiol receptor levels in human endometrium. Journal ClinicalEndocrinology and Metabolism 41:402, 1975) and also acts to downregulateendometrial estrogen receptors possibly by induction of an estrogenreceptor regulatory factor (see Leavitt W. W., Okulicz W. C., McCrackenJ. A., Schramm W. S. and Robidoux W. F., Jr. Rapid recovery of nuclearestrogen receptor and oxytocin receptor in the ovine uterus followingprogesterone withdrawal. Journal Steroid Biochemistry 22:686, 1985).

These physiologic changes can be reproduced pharmacologically as shownby the induction of estrogen and progestin receptors in postmenopausalwomen by the administration of ethinyl estradiol (see Kreitmann B.,Bugat R. and Bayard F. Estrogen and progestin regulation of theprogesterone receptor concentration in human endometrium. JournalClinical Endocrinology and Metabolism 49:926, 1979). Neumannova et al.(see Short-term effects of tamoxifen, medroxyprogesterone acetate, andtheir combination on receptor kinetics and 17beta-hydroxysteroiddehydrogenase in human endometrium. Obstetrics and Gynecology 66:695,1985) have also demonstrated that administration of medroxyprogesteroneacetate in estrogen-primed women decreases the concentration ofendometrial progestin receptors while at the same time increasing theactivity of 17beta-hydroxysteroid dehydrogenase, the enzyme which isresponsible for metabolism of estradiol to the less potent estrone.

A complex interaction occurs between estrogen and progesterone orprogestin in the human endometrium with the progestins acting asanti-estrogens. Estrogen and progestin interactions are also dynamic.For example, estrogen administration increased the concentration of bothestrogen and progestin receptors to peak levels, 7 times above baseline,within 3 days (see Ekert R. L. and Katzenellenbogen B. S. Humanendometrial cells in primary tissue culture: Modulation of theprogesterone receptor level by natural and synthetic estrogens in vitro.Journal Clinical Endocrinology and Metabolism 52:699, 1981). Athree-fold increase in receptor concentrations occurred within one day.Normal physiologic levels of progesterone in the first 3 days of theluteal phase resulted in a rapid and significant decrease in estrogenreceptor number (see Kreitmann-Gimbal B., Bayard F., Nixon W. E. andHodgen G. D. Patterns of estrogen and progesterone receptors in monkeyendometrium during the normal menstrual cycle. Steroids 35:471, 1980).Exogenous administration of progesterone to cynomolgous macaquessignificantly suppressed estrogen receptors within 1 to 2 days (see WestN. B. and Brenner R. M. Progesterone-mediated suppression of estradiolreceptors in cynomolgous macaque cervix, endometrium and oviduct duringsequential estradiol-progesterone treatment. Journal SteroidBiochemistry 22:29, 1985) and medroxyprogesterone acetate was able tosignificantly suppress progestin receptor levels in premenopausal womenwithin 4 hours (see Neumannova M., Kauppila A., Kivinen S. and Vihko R.Short-term effects of tamoxifen, medroxyprogesterone acetate, and theircombination on receptor kinetics and 17beta-hydroxysteroid dehydrogenasein human endometrium, Obstetrics and Gynecology 66:695, 1985). Incontrast, progesterone withdrawal in the presence of constant estrogenlevels has been shown to result in rapid (6 to 12 hours) recovery ofnuclear estrogen receptors in sheep endometrium, associated with anestrogen induced biological response, i.e. production of oxytccinreceptors (see Leavitt W. W., Okulicz W. C., McCracken J. A., Schramm W.S. and Robidoux W. F.: Jr. Rapid recovery of nuclear estrogen receptorand oxytocin receptor in the ovine uterus following progesteronewithdrawal. Journal Steroids and Biochemistry 22:686, 1985). A similarphenomenon occurs in pregnant guinea pigs when estrogen levels riserelative to progesterone levels prior to parturition (Biology andReproduction 22:1106, 1980) see Alexandrova, M. and Soloff, M. S.Oxytocin receptors and parturition in the guinea pig.

Therefore, it appears that estrogen acts to stimulate both estrogen andprogestin receptor concentrations and to induce sensitivity of theendometrium to both estrogen and progestin. Progesterone or progestinexerts an anti-estrogen action by decreasing the concentration ofestrogen receptors and by increasing 17beta-hydroxysteroid dehydrogenaseactivity in endometrial tissue. However, it appears that the stimulatoryeffects of progesterone on human endometrial function are of shortduration probably because of a self-provoked downregulation of progestinreceptors (see Neumannova M., Kauppila A., Kivinen S. and Vihko R.Short-term effects of tamoxifen, medroxyprogesterone acetate, and theircombination on receptor kinetics and 17beta-hydroxysteroid dehydrogenasein human endometrium, Obstetrics and Gynecology 66:695, 1985; WhiteheadM. I., Townsen P. T., Pryce-Davies J. et al. Effects of estrogens andprogestins on the biochemistry and morphology of the postmenopausalendometrium. New England Journal of Medicine. 305:1599, 1981). Forexample, the effect of progesterone on 17beta-hydroxysteroiddehydrogenase peaks at 3 days and is then followed in 2 to 3 weeks bysuppression of the enzyme (see Whitehead M. I., Townsend P. T.,Pryce-Davies J. et al. Effects of estrogens and progestins on thebiochemistry and morphology of the postmenopausal endometrium. NewEngland Journal of Medicine 305:1599, 1981).

Current hormonal replacement consists of continuous (daily or cyclic)(example days 1-25 of each month) estrogen administration with theaddition of a progestin for 10-13 days (example days 13-25) each month.This type of replacement regimen is effective in preventing menopausalsymptoms and at the same time, protects the endometrium against thedevelopment of hyperplasia or adenocarcinoma. However, the cyclicadministration of a progestin leads to a scheduled withdrawal bleed orperiod in 65-75% of women (see Hellberg D., Nilsson S. Comparison of atriphasic estradiol/norethisterone acetate preparation with and withoutestriol component in the treatment of climacteric complaints; Maturitas5:233, 1984: Christensen M. S., Hagen C., Christiansen C., Transbol I.Dose response evaluation of cyclic estrogen/gestagen in postmenopausalwomen: Placebo controlled trial of its gynecologic and metabolicactions. American Journal of Obstetrics and Gynecology. 144:873, 1982).This withdrawal bleeding is usually not welcomed by the patient and canlead to problems with compliance. Also because the progestinadministration is preceded by up to 13-16 days of unopposed estrogentherapy with endometrial proliferation and estrogen and progestinreceptor induction, it is possible that a high dose of progestin isrequired to antagonize these effects resulting in a greater chance ofside effects and adverse metabolic effects. Newer continuous low doseestrogen and progestin regimens for hormonal replacement may avoid theproblem of withdrawal bleeding (see Magos A. L., Brincatt M., O'Dowd T.,et al. Amenorrhea and endometrial atrophy following continuous oralestrogen and progestogen therapy in postmenopausal women. Maturitas6:145, 1984). However, daily administration of a progestin in theseregimens induces depletion of both estrogen and progestin receptorsresulting in endometrial atrophy which may be associated withbreakthrough bleeding. Since abnormal bleeding in a postmenopausal womanis known to be associated with endometrial carcinoma, it must beinvestigated by endometrial sampling for hypertrophy usually by D&C.Daily administration of a progestin also raises the concern that thefavourable effects of estrogen on HDL cholesterol metabolism will beadversely affected with a fall in HDL cholesterol (see Notelovitz M.,Gudat J. C., Ware M. D., Dougherty M. C. British Journal of Obstetricsand Gynecology. 90:171, 1983).

The present invention provides a pharmaceutical preparation foradministration to a female of child bearing age or older in whom ovarianestrogen and progesterone production has been interrupted either becauseof natural menopause, surgical, radiation, or chemical ovarian ablationor extirpation or premature ovarian failure, which comprises a pluralityof unit dosages, each unit dosage for continuous consecutive dailyadministration and comprising combinations of estrogen and progestinselected from a combination with relatively dominant estrogen activityand a combination with relatively dominant progestin activity, with aplurality of dominant estrogen dosages being alternated with pluralityof dominant progestin dosages, and each unit dosage also comprising apharmaceutically acceptable inert carrier when required.

In another aspect, the invention provides a method of hormonalreplacement therapy for administration to a female in need of suchtreatment, in particular to a female of child bearing age or older inwhom ovarian estrogen and progesterone production has been interruptedeither because of natural menopause, surgical, radiation, or chemicalovarian ablation or extirpation or premature ovarian failure, whichcomprises administering continuously and consecutively, in dailysequence, a plurality of daily unit dosages comprising combinations ofestrogen and progestin, selected from a combination with relativelydominant estrogen activity and a combination with relatively dominantprogestin activity, a plurality of the dominant estrogen activity unitdosages being alternated with a plurality of the dominant progestinactivity unit dosages.

The hormonal replacement formulation of the present invention results inthe absence of withdrawal bleeding; intermittent increases in estrogenactivity; and stimulation of endometrial growth and progestin receptors.The previously described push/pull activity not only keeps endometrialactivity within a narrow range depending on the number of days ofestrogenic and progestagenic activity, but also maintains a stableendometrium resulting in the absence of breakthrough or withdrawalbleeding.

This hormonal replacement formulation allows better progestationaleffects with less progestin. With the current formulation the dose ofprogestin is significantly decreased compared with a preparationcontaining constant daily administration of a progestin. A total steroiddosage is achieved which is similar to or even lower than that of theepresent cyclic method of administering estrogen and progestin forhormonal replacement therapy of ovarian failure.

The estrogens which may be employed as a component in the regimens ofthis invention may be any of those conventionally available. Typically,the estrogen may be selected from the group comprising synthetic andnatural estrogens. The synthetic estrogens may be selected from, forexample, ethinyl estradiol, mestranol and quinestranol. Particularly ofinterest are 17alpha-ethinylestradiol and esters and ethers thereof. Thepreferred estrogen is 17alpha-ethinylestradiol. The natural estrogensmay include, for example, conjugated equine estrogens, estradiol-17beta,estradiol valerate, estrone, piperazine estrone sulphate, estriol,estriol succinate, and polyestrol phosphate.

The progestin component may be any progestationally active compound.Thus, the progestin may be selected from progesterone and itsderivatives such as, for example, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17alpha-ethinyltestosterone andderivatives thereof, 17alpha-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone, dl-norgestrel,d-17alpha-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, desogestrel and norgestimate. Preferred progestinsare norethindrone, d-norgestrel and norgestimate.

In a preferred form of the invention, the plurality of dosages maycomprise from one to five unit dosages, but preferably three unitdosages are employed. Thus, in a preferred form of the invention, threeunit dosages of relatively dominant estrogen activity are alternatedwith three unit dosages of relatively dominant progestin activity and soon for a total of twenty-one or twenty-four unit dosages. Four or sevenunit dosages which are free of hormone are included to approximate thenatural twenty-eight day menstrual cycle of the female. These pills maycomprise a placebo or any other hormone-free agent. Examples of suitablealternative agents include vitamins, such as iron supplements. Where thetotal unit dosages do not comprise multiples of three, an appropriatenumber of hormone-free unit dosages may be included to make up the totalrequired units.

Generally, the quantities of estrogen and progestin incorporated in theformulation of the invention are dependent on the type of estrogen orprogestin selected. However, the quantities employed are generally lessthan those used in the currently marketed formulations for reasonsmentioned earlier. In preferred formulations, the estrogen level is keptconstant, while the progestin level is adjusted up or down to producethe required estrogen or progestin dominance. The selection of quantityis dependent on the type of estrogen or progestin since each hormone hasits own specific activity.

Typically in the hormone replacement formulations, the amount ofestrogen per unit dose may range from a minimum of about 0.3 mg ofestrone sulphate or its equivalent to a maximum of about 2.5 mg ofestrone sulphate or its equivalent. The amount of progestin per unitdosage may range from a minimum of 0 mg to a maximum of about 5 mg ofnorethindrone or its equivalent.

Some preferred combinations include the following:

1. Three units dosages of 0.75 mg piperazine estrone sulphatealternating with three unit dosages of 0.75 mg of piperazine estronesulphate with 0.35 mg of norethindrone.

2. Three unit dosages of 0.75 mg piperazine estrone sulphate and 0.15 mgof norethindrone alternating with three unit dosages of 0.75 mg ofpiperazine estrone sulphate and 0.35 mg of norethindrone.

The above combinations may also be grouped into three's and four's,starting with either three or four day groups and ending with the other.

The formulations of the invention may be administered orally, preferablyin tablet form, parenterally, sublingually, transdermally,intravaginally, intranasally or buccally. The method of administrationdetermines the types of estrogens and progestins useful in theformulation, as well as the amounts per unit dosage.

Methods for transdermal administration including the associated methodsfor manufacturing such systems are well known in the art. In thisconnection, reference may be had to U.S. Pat. Nos. 4,752,478, 4,685,911,4,438,139 and 4,291,014.

Generally speaking, the formulations are prepared according toconventionally known procedures in accordance with the method ofadministration. Thus, the active ingredients are prepared according toknown methods in a pharmaceutically acceptable form for administration.These ingredients, in their required quantities are combined with theappropriate pharmaceutical carriers such as additives, vehicles and/orflavour ameliorating substances. These substances may be referred to asdiluents, binders and lubricants. Gums, starches and sugars are alsocommon terms. Typical of these types of substances or excipients arepharmaceutical grades of mannitol, lactose starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate and the like. The active ingredient(s) may comprise from about0.01% by weight to about 99.99% by weight of the total formulation andthe remainder comprises the pharmaceutically acceptable carrier. Thepercentage of active ingredient(s) may vary according to the deliverysystem or method of administration and is chosen in accordance withconventional methods known in the art.

Thus, the active ingredients are compounded with the chosen carrier andin for example the case of a tablet form, placed in a tablet moldingapparatus to form the tablets which are subsequently packaged inaccordance with the chosen regimen.

In the oral form of the formulation, the contraceptives are preferablyproduced in the form of a pharmaceutical kit or package, with the dailydosages arranged for proper sequential administration. Thus, in anotheraspect, the present invention also provides a pharmaceutical packagewhich contains combination-type contraceptives in multiple dosage unitsin a synchronized, fixed sequence, wherein the sequence or arrangementof the dosage units corresponds to the stages of daily administration.

Preferably, such packages are in the form of a transparent package withtwenty-eight dosage units arranged sequentially and consisting oftwenty-one or twenty-four tablets containing the combinedestrogen/progestin formulation set up for the cyclical regimen of theinvention and seven or four placebos thereafter.

Preferably the placebo tablets and tablets containing the hormones aredifferent colours or shapes. Data indications may be provided on thepackaging. The packaging may be a tube or box or a strip. The box may becircular, square, or otherwise shaped with the tablets beingaccommodated separately therein for ease of administration. Dateindications may appear adjacent each tablet corresponding with the dayson which each tablet is to be taken. Some indication of the sequence inwhich the tablets are to be taken preferably appears on the packagingregardless of its form.

In the following examples, specific embodiments of the present inventionare set forth. These are meant to be illustrative of the invention andare not meant to limit it in any way. All parts and percentages are byweight, unless indicated otherwise.

EXAMPLES ILLUSTRATING THE METHOD OF CONTRACEPTION Example 1

Three-day phases of unit dosages of 17alpha-ethinyl-estradiol(EE) 0.035mg. and norethindrone (NET) 0.5 mg. alternating with three-day phases ofunit dosages of EE 0.035 mg. and NET 0.75 mg. for a total of 7 phases(21 days or 21 unit dosages) beginning and ending with the NET 0.5 mg.combination.

Example 2

Three-day phases (unit dosages of EE 0.035 mg. and NET 0.5 mg.)alternating with three-day phases of EE 0.035 mg. and NET 0.35 mg.,beginning and ending with the 0.5 mg. combination

Example 3

Two-day phases of unit dosages of EE 0.035 mg alternating with unitdosages of EE 0.035 mg and NET 0.35 mg, beginning and ending with thefirst unit dosage and running for 24 days total.

Example 4

Three-day phases of unit dosages of EE 0.035 mg and NET 0.15 mgalternating with EE 0.035 mg and NET 0.35 mg and running for 24 daystotal.

Example 5

Three-day and four-day phases of each of the above combinations as setforth in Examples 1 and 2, starting with either three or four-day phasesand ending with the other.

Example 6

Four-day and three-day phases are prepared, starting with a four-dayunit dosage of 0.5 rag. NET and 0.035 mg. EE and ending with 0.75 mg.NET and 0. 035 mg. EE.

Example 7

Three-day and four-day phases of formulations starting with a three-dayphase of 0.35 mg. NET with 0.035 mg. EE and ending with a four-day phaseof 0.5 mg. NET and 0. 035 mg. EE.

Example 8

One-day alternating phases using the unit dosages set forth in Examples1 and 2.

Example 9

Two-day alternating phases ending or beginning with a single three-dayphase, using the unit dosage formulations set forth in Examples 1 or 2.

Example 10

Three-day phases of EE 0.035 mg. and levo-norgestrel (D-norgestrel) 0.05mg. alternating with 3-day phases of EE 0.035 mg. and levonorgestrel0.075 mg.

Example 11

Three-day phases of EE 0.035 mg. and norgestimate 0.05 mg. alternatingwith EE 0.035 mg. and norgestimate 0.075 mg.

Example 12

Three-day phases of EE 0.035 mg. and norgestimate 0.05 mg. alternatingwith EE 0.035 and norgestimate 0.035 mg.

Examples 13 & 14

One formulation was administered to two women for a total of threecycles to establish that cycle control, in terms of breakthroughbleeding, is acceptable. The test formulation consisted of three unitdosages of 0.035 mg. of 17alpha-ethinylestradiol and 0.5 mg. ofnorethindrone alternating with three unit dosages of 0.035 mg. of17alpha-ethinylestradiol and 0.75 mg. of norethindrone for a total ofseven groups of three, beginning and ending with the 0.5 mg. ofnorethindrone combination.

Example 13

A twenty-three year old nulliparous woman who had not taken any hormonalformulation including oral contraceptives for three months agreed totake the test formulation of the invention for two cycles. The subjectwas in good health and did not smoke. The subject had nocontraindications to the use of oral contraceptives and her menstrualcycles were regular. The subject started the test formulation on thefifth day of her cycle (onset of menstruation is considered day 1) fortwenty-one consecutive days (first cycle), followed by a seven dayinterval which was free of any hormone and then restarted the testformulation for another twenty-one days (second cycle). In the firstcycle the subject had no bleeding or spotting while taking the testformulation and had a withdrawal bleed starting on the second day of thehormone free interval. The withdrawal bleed lasted for five days and waslighter than a normal menstrual period consisting of reddish-brownspotting. There was no discomfort associated with the withdrawalbleeding. In the second cycle, the subject was also free of bleeding orspotting while taking the test formulation and again had a brownish,very light withdrawal bleed which began two days after stopping the testformulation and lasted for six days. The subject experienced no sideeffects during the two test cycles.

Example 14

The subject was a healthy, twenty-seven year old nulliparous woman whowas currently taking a commercially available oral contraceptiveformulation containing 17alpha-ethinylestradiol and dl-norgestrel(Tripbasil (Trade mark of Wyeth Pharmaceuticals)). The subject agreed totake the test formulation of the invention for one cycle. The subjectstarted the test formulation after a seven day hormone free intervalfollowing the last Tripbasil tablet. The test formulation was taken fortwenty-one days followed by a seven day drug free interval. The subjecthad no spotting or bleeding during the time she took the testformulation and experienced a withdrawal bleed which began two daysafter stopping the test formulation. The withdrawal bleeding lasted fourdays, was painless and was the same amount and colour as a normalmenstrual period for the subject. The subject had no side effects duringthe test formulation.

Both subjects found the test formulation to be acceptable in terms ofcycle control, side effects and menstrual bleeding.

EXAMPLES ILLUSTRATING THE HORMONE-REPLACEMENT THERAPY Example 15

Three-day phases of unit dosages of 0.75 mg piperazine estrone sulphatealternating with three-day phases of unit dosages of estrone sulphate0.75 mg and NET 0.35 mg given continuously or orally.

Example 16

Three-day phases (unit dosages of estrone sulphate 0.75 mg andnorethindrone 0.15 mg) alternating with three-day phases of estronesulphate 0.75 mg and norethindrone 0.35 mg given continuously or orally.

Example 17

Three-day phases of oral micronized 17betaestradiol 1 mg alternatingwith three-days of 17beta-estradiol 1 mg and norethindrone 35 mg.

Example 18

Three-day phases of transdermal 17beta-estradiol (100 μg/day)alternating with three-days of transdermal 17beta-estradiol (100 μg/day)and transdermal norethindrone (0.35 mg/day ) given continuously.

Example 19

Three-day phases of estrone sulphate 1.25 mg alternating with three-dayphases of estrone sulphate 1.25 mg and norethindrone 0.35 mg givencontinuously or orally.

Example 20

Three-day phases of estrone sulphate 1.25 mg alternating with three-dayphases of estrone sulphate 1.25 mg and norethindrone 0.5 mg givencontinuously or orally.

Example 21

One-day or two-day alternating phases using the unit dosages set forthin Examples 15 and 16 given continuously or orally.

Example 22

Three-day phases of estrone sulphate 0.75 mg alternating with three-dayphases of estrone sulphate 0.75 mg and norgestimate 0.050 mg givencontinuously or orally.

Example 23

Three-day and four-day phases of each of the combinations as set forthin Examples 13 and 14, starting with either a 3- or 4-day phase andgiven continuously or orally.

Example 24

Two-day and three-day phases of each of the combinations as set forth inExamples 15 and 16, starting with either a two- or three-day phase andgiven continuously or orally.

Example 25

A pharmaceutical preparation is prepared in which three days oftransdermal 17β-estradiol (0.1 mg/day) with norethindrone (0.15 mg/day)are alternated with transdermal 17-estradiol (0.1 mg/day) withnorethindrone (0.35 mg/day).

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material or composition of matter, process,process step or steps, or then present objective to the spirit of thisinvention without departing from its essential teachings.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A pharmaceuticalpreparation for administration to a female in need of hormonereplacement therapy comprising repeating cycles of a pharmaceuticalregimen, each cycle comprising a series of from twenty to thirty-fiveconsecutive daily unit doses arranged in alternating estrogen dominantphases and progestin dominant phases, each phase consisting of from oneto four consecutive daily unit doses, wherein the daily unit doses ofsaid estrogen dominant phases containi) an amount of a substanceexhibiting estrogen activity or ii) an amount of a substance exhibitingestrogen activity and an amount of a substance exhibiting progestinactivity, and the daily unit doses of said progestin dominant phasescontain an amount of a substance exhibiting estrogen activity and anamount of a substance exhibiting progestin activity, the amount of saidsubstance exhibiting progestin activity being alternately increased inthe progestin dominant phases to provide daily unit doses exhibitingprogestin dominant activity and decreased in the estrogen dominantphases to provide daily unit doses exhibiting estrogen dominantactivity, and wherein the amount of substance exhibiting estrogenactivity per unit dose exhibits an estrogen activity equivalent to fromabout 0.3 to about 2.5 mg of piperazine estrone sulfate, and the amountof substance exhibiting progestin activity per unit dose ranges from 0to an amount which exhibits a progestin activity equivalent to about 5mg of norethindrone.
 2. A pharmaceutical preparation according to claim1 wherein the daily unit doses of said estrogen dominant phases containan amount of substance exhibiting progestin activity ranging from 0 toan amount which exhibits a progestin activity equivalent to 0.5 mg ofnorethindrone, and the daily unit doses of said progestin dominantphases contain an amount of substance exhibiting progestin activitywhich exhibits a progestin activity equivalent to from 0.35 to 5 mgnorethindrone, the amount of substance exhibiting progestin activitybeing greater in said progestin dominant phases than in said estrogendominant phases.
 3. A pharmaceutical preparation according to claim 1,wherein all of said daily unit doses contain a uniform amount of saidsubstance exhibiting estrogen activity.
 4. A pharmaceutical preparationaccording to claim 1, wherein the daily unit doses of said estrogendominant phases are free of substance exhibiting progestin activity. 5.A pharmaceutical preparation according to claim 1, wherein saidsubstance exhibiting estrogen activity is selected from the groupconsisting of 17α-ethinyl estradiol, 17β-estradiol, 17β-estradiolvalerate, conjugated equine estrogens, piperazine estrone sulfate, andestropipate, and said substance exhibiting progestin activity isselected from the group consisting of norethindrone, desogestrel,levo-norgestrel, norgestimate, progesterone, medroxy-progesteroneacetate, gestodene, and cyproterone acetate.
 6. A pharmaceuticalpreparation according to claim 1, wherein said daily unit doses are in aform selected from the group consisting of orally administrable form,transdermally administrable form, and buccally administrable form.
 7. Apharmaceutical preparation according to claim 1, comprising a series ofconsecutive daily unit doses arranged in estrogen dominant phases of twodaily unit doses each alternating with progestin dominant phases of twodaily unit doses each.
 8. A pharmaceutical preparation according toclaim 1, comprising a series of consecutive daily unit doses arranged inestrogen dominant phases of three daily unit doses each alternating withprogestin dominant phases of three daily unit doses each.
 9. Apharmaceutical preparation according to claim 1, wherein saidpreparation is a hormone replacement therapy preparation, and each ofsaid daily unit doses contains an amount of substance exhibitingestrogen activity which exhibits an estrogen activity equivalent to from0.3 to 2.5 mg of piperazine estrone sulfate, and an amount of substanceexhibiting progestin activity ranging from 0 to an amount which exhibitsa progestin activity equivalent to 5 mg norethindrone.
 10. Apharmaceutical preparation according to claim 9, wherein each estrogendominant phase consists of three orally administrable daily unit doseseach containing 0.75 mg piperazine estrone sulfate, and each progestindominant phase consists of three orally administrable daily unit doseseach containing 0.75 mg piperazine estrone sulfate and 0.35 mgnorethindrone.
 11. A pharmaceutical preparation according to claim 9,wherein each estrogen dominant phase consists of three transdermallyadministrable daily unit doses each releasing 0.1 mg 17β-estradiol, andeach progestin dominant phase consists of three transdermallyadministrable daily unit doses each releasing 0.1 mg 17β-estradiol and0.35 mg norethindrone.
 12. A pharmaceutical preparation according toclaim 9, wherein each estrogen dominant phase consists of threetransdermally administrable daily unit doses each releasing 0.1 mg17β-estradiol and 0.15 mg norethindrone, and each progestin dominantphase consists of three transdermally administrable daily unit doseseach releasing 0.1 mg 17β-estradiol and 0.35 mg norethindrone.
 13. Apharmaceutical preparation according to claim 9, wherein three unitdoses of 1.0 mg of 17-estradiol are alternated with three unit doses of1.0 mg of 17-estradiol and 0.35 mg norethindrone.
 14. A pharmaceuticalpackage containing a least one cycle of a pharmaceutical regimen foradministration to a female in need of hormone replacement therapy, eachsaid cycle comprising repeating cycles of a pharmaceutical regimen, eachcycle comprising a series of from twenty to thirty-five consecutivedaily unit doses arranged in alternating estrogen dominant phases andprogestin dominant phases, each phase consisting of from one to fourconsecutive daily unit doses, wherein the daily unit doses of saidestrogen dominant phases contain i) an amount of a substance exhibitingestrogen activity or ii) an amount of a substance exhibiting estrogenactivity and an amount of a substance exhibiting progestin activity, andthe daily unit doses of said progestin dominant phases contain an amountof a substance exhibiting estrogen activity and an amount of a substanceexhibiting progestin activity, the amount of said substance exhibitingprogestin activity being alternately increased in the progestin dominantphases to provide daily unit doses exhibiting progestin dominantactivity and decreased in the estrogen dominant phases to provide dailyunit doses exhibiting estrogen dominant activity, and wherein the amountof substance exhibiting estrogen activity per unit dose exhibits anestrogen activity equivalent to from about 0.3 to about 2.5 mg ofpiperazine estrone sulfate, and the amount of substance exhibitingprogestin activity per unit dose ranges from 0 to an amount whichexhibits a progestin activity equivalent to about 5 mg of norethindrone.15. A pharmaceutical package according to claim 14, wherein the dailyunit doses of said estrogen dominant phases contain an amount ofsubstance exhibiting progestin activity ranging from 0 to an amountwhich exhibits a progestin activity equivalent to 0.5 mg ofnorethindrone, and the daily unit doses of said progestin dominantphases contain an amount of substance exhibiting progestin activitywhich exhibits a progestin activity equivalent to from 0.35 to 5 mgnorethindrone, the amount of substance exhibiting progestin activitybeing greater in said progestin dominant phases than in said estrogendominant phases.
 16. A pharmaceutical package according to claim 14,wherein all of said daily unit doses contain a uniform amount of saidsubstance exhibiting estrogen activity.
 17. A pharmaceutical packageaccording to claim 14, wherein the daily unit doses of said estrogendominant phases are free of substance exhibiting progestin activity. 18.A pharmaceutical package according to claim 14, wherein said substanceexhibiting estrogen activity is selected from the group consisting of17α-ethinyl estradiol, 17βestradiol, 17β-estradiol valerate, conjugatedequine estrogens, piperazine estrone sulfate, and estropipate, and saidsubstance exhibiting progestin activity is selected from the groupconsisting of norethindrone, desogestrel, levo-norgestrel, norgestimate,progesterone, gestodene, cyproterone acetate and medroxy-progesteroneacetate.
 19. A pharmaceutical package according to claim 14, whereinsaid daily unit doses are in a form selected from the group consistingof orally administrable form, transdermally administrable form, andbuccally administrable form.
 20. A pharmaceutical package according toclaim 14, containing a series of consecutive daily unit doses arrangedin estrogen dominant phases of two daily unit doses each alternatingwith progestin dominant phases of two daily unit doses each.
 21. Apharmaceutical package according to claim 14, containing a series ofconsecutive daily unit doses arranged in estrogen dominant phases ofthree daily unit doses each alternating with progestin dominant phasesof three daily unit doses each.
 22. A pharmaceutical package accordingto claim 14, containing a hormone replacement therapy preparation,wherein each of said daily unit doses contains an amount of substanceexhibiting estrogen activity equivalent to from 0.3 to 2.5 mg ofpiperazine estrone sulfate, and an amount of substance exhibitingprogestin activity ranging from 0 to an amount which exhibits aprogestin activity equivalent to 5 mg norethindrone.
 23. Apharmaceutical package according to claim 22, wherein each estrogendominant phase consists of three orally administrable daily unit doseseach containing 0.75 mg piperazine estrone sulfate, and each progestindominant phase consists of three orally administrable daily unit doseseach containing 0.75 mg piperazine estrone sulfate and 0.35 mgnorethindrone.
 24. A pharmaceutical package according to claim 22,wherein each estrogen dominant phase consists of three transdermallyadministrable daily unit doses each releasing 0.1 mg 17β-estradiol, andeach progestin dominant phase consists of three transdermallyadministrable daily unit doses each releasing 0.1 mg 17β-estradiol and0.35 mg norethindrone.
 25. A pharmaceutical package according to claim22, wherein each estrogen dominant phase consists of three transdermallyadministrable daily unit doses each releasing 0.1 mg 17β-estradiol and0.15 mg norethindrone, and each progestin dominant phase consists ofthree transdermally administrable daily unit doses each releasing 0.1 mg17β-estradiol and 0.35 mg norethindrone.
 26. A pharmaceutical packageaccording to claim 22, wherein three unit doses of 1.0 mg of17β-estradiol are alternated with three unit doses of 1.0 mg of17β-estradiol and 0.35 mg of norethindrone.